BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia
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To conduct a multicenter, randomized, placebo-controlled, double-blind, phase II study of BAY41-6551 (NCT01004445), an investigational drug–device combination of amikacin, formulated for inhalation, and a proprietary Pulmonary Drug Delivery System, for the treatment of Gram-negative pneumonia in mechanically ventilated patients.
Sixty-nine mechanically ventilated patients with Gram-negative pneumonia, a clinical pulmonary infection score ≥6, at risk for multidrug-resistant organisms, were randomized to BAY41-6551 400 mg every 12 h (q12h), 400 mg every 24 h (q24h) with aerosol placebo, or placebo q12h for 7–14 days, plus standard intravenous antibiotics. The combined primary endpoint was a tracheal aspirate amikacin maximum concentration ≥6,400 μg/mL (25 × 256 μg/mL reference minimum inhibitory concentration) and a ratio of area under the aspirate concentration–time curve (0–24 h) to minimum inhibitory concentration ≥100 on day 1.
The primary endpoint was achieved in 50% (6/12) and 16.7% (3/18) of patients in the q12h and q24h groups, respectively. Clinical cure rates, in the 48 patients getting ≥7 days of therapy, were 93.8% (15/16), 75.0% (12/16), and 87.5% (14/16) in the q12h, q24h, and placebo groups, respectively (p = 0.467). By the end of aerosol therapy, the mean number of antibiotics per patient per day was 0.9 in the q12h, 1.3 in the q24h, and 1.9 in the placebo groups, respectively (p = 0.02 for difference between groups). BAY41-6551 was well tolerated and attributed to two adverse events in one patient (mild bronchospasm).
BAY41-6551 400 mg q12h warrants further clinical evaluation.
KeywordsBAY41-6551 Gram-negative pneumonia Inhaled amikacin Tracheal concentrations Ventilator-associated pneumonia
The work of the principal investigators and their study site teams in recruiting patients and conducting the study is gratefully acknowledged. The principal investigators were: A. Anzueto, South Texas Veterans Administration Hospital, San Antonio, TX; K. Guntupalli, Baylor College of Medicine, Houston, TX; R. Hite, Wake Forest University School of Medicine, Winston-Salem, NC; J. Kennedy Jr., VA Medical Center, Birmingham, AL; J. O’Brian, Davis Heart & Lung Research Institute, Columbus, OH; M. Ott, Melbourne Internal Medicine Associates, Melbourne, FL; T. Smith, Albany Medical Center, Albany, NY; J. Carlet, Hôpital Saint Joseph, Paris, France; J. Chastre, Hôpital Pitié Salpétrière, Paris, France; M. Chavel, CHU Dupuytren, Limoges, France; J-Y. Fagon, Hôpital Européen Georges Pompidou, Paris, France; A. Mercat, Centre Hospitalier Universitaire d’Angers, Angers, France; B. Veber, CHU Charles Nicolle, Rouen, France; M. Wolf, Hôpital Bichat-Claude Bernard, Paris, France; M. Daguerre Talou, Hospital Universitario Principe de Asturias, Alcalá de Henares (Madrid), Spain; A. Torres Martí, Hospital Clinic i Provincial, Barcelona, Spain; F. Álvarez Lerma, Hospital del Mar, Barcelona, Spain; A. Martínez Pellús, Hospital Universitario Virgen de la Arrixaca, El Palmar, Spain; J. Cobo Reinoso, Hospital Universitario Ramón y Cajal, Madrid, Spain; and F. Martínez Sagasti, Hospital Clinico San Carlos, Madrid, Spain. The authors would also like to acknowledge Susanna Ryan of Chameleon Communications International Ltd who provided medical writing assistance with funding from Bayer HealthCare. This work was supported by Nektar Therapeutics.
Conflict of interest
This study and the data analysis were sponsored by Nektar Therapeutics. In August 2007, Nektar Therapeutics entered into a commercial agreement with Bayer HealthCare for the joint development of BAY41-6551. A clinical study report was made available to all authors in addition to statistical support for further data queries and the journal has had permission to review the data on request. MN has received consulting fees from Bayer HealthCare Pharmaceuticals Inc. and Nektar Therapeutics, fees from Bayer HealthCare Pharmaceuticals Inc. for the development of education presentations, travel support for meetings, and lectures from Bayer HealthCare Pharmaceuticals Inc., and a research grant from Bayer HealthCare Pharmaceuticals Inc. for the current study. JC has received fees from Bayer HealthCare Pharmaceuticals Inc. and Nektar Therapeutics for lectures, and a research Grant from Nektar Therapeutics. KC was an employee of Nektar Therapeutics during the conduct of the study and is now employed by Novartis Pharmaceuticals Corporation. JBF was an employee of Nektar Therapeutics during the conduct of the study and is now an employee of Aerogen Limited, a stockholder in Nektar Therapeutics and a patent holder for an aerosol delivery system for mechanical ventilation. C-EL and MSG have no conflicts of interest.
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